The onset of sex bias in the expression of depressive illness after the onset of puberty, as well as anecdotal studies suggesting an association between mood and cyclic gonadal steroid changes suggest that gonadal axis hormones may modulate the onset and course of depression. Hormones of the hypothalamic pituitary adrenal (HPA) axis have been demonstrated to affect the hypothalamic pituitary gonadal axis, particularly the secretion of gonadotropin releasing hormone (GnRH) from the hypothalamus. Our previous studies on reproductive axis in pre- menopausal women with major depression found lower estradiol in the follicular phase. In addition, we found suggestions of decreased LH amplitude, mean levels and half-life during the follicular phase in depressed women, but we had inadequate power (n=12) to demonstrate significant differences. Finally, it appeared that several of these abnormalities were related to mean cortisol levels. We seek to confirm these findings in a larger group of depressed women studied during the first 10 days of the menstrual cycle along with age and menstrual cycle day matched control women. We will also examine the links between these abnormalities and mean cortisol. Furthermore, neuroimaging data, post-mortem suicide data and treatment data support a role for serotonin in the etiology of depression. Gender differences in the serotonin systems have been demonstrated in humans and estradiol has been shown to influence these systems in animal studies. Our underlying model is that both estradiol and cortisol modulate 5HT1a binding and thereby influence susceptibility to depression in women. To test this model, we propose to: 1) evaluate HPG hormones as well as cortisol in drug free depressed patients and matched controls; 2) examine the effects of estradiol supplementation on 5HT1a binding in the raphe, hippocampus and cortex in normal women as measured by [11C]-WAY100635 and 3) conduct correlational analyses on the relationship between estradiol, cortisol and 5HT1a BP binding in the raphe, hippocampus and cortex in normal women and women with MDD. PUBLIC HEALTH RELEVANCE: Women are more likely to suffer from depression, and at times when estrogen levels are low or falling, such as puberty, following childbirth and in the transition to menopause, depression rates increase. These findings suggest that estrogen affects mood. This project will evaluate whether women with depression show low estrogen levels and if the changes in estrogen are accompanied by changes in serotonin binding in the brains of women with major depression